Regioselective electrophilic aromatic borylation as a method for synthesising sterically hindered benzothiadiazole fluorophores

Regioselective stepwise phenylation of 4,7-diarylbenzo[c][1,2,5]thiadiazole fluorophores has been achieved through a facile one-pot, three-step synthetic strategy involving sequential borylation, hydroxydechlorination and Suzuki–Miyaura cross-coupling reactions. Crucial to the selectivity was the use of BCl3 to regioselectively install a boronic acid group in the ortho-position of only one of the diaryl groups. The subsequent introduction of ortho-phenyl groups through Suzuki–Miyaura cross-coupling gave rise to twisted structures with hindered intramolecular rotation, providing a structural lever with which the fluorophore absorption and emission properties could be adjusted.


Introduction
In recent years, organic p-conjugated electron donor-acceptor (D-A) species have garnered signicant interest due to their utility in organic light harvesting and emitting applications, such as organic photovoltaics, 1 photocatalysts, 2 and uorophores. 3 The successful design of an efficient light harvesting electron D-A system is underpinned by a fundamental understanding of the structure-property relationship of a particular combination of electron donor and acceptor building blocks. Amongst the various electron acceptor building blocks, the benzo[c] [1,2,5]thiadiazole (BTZ) group has emerged as a promising candidate, mainly due to its strongly electron accepting nature in combination with its photostability. [4][5][6] Combination of the BTZ group with various donor groups has led to light harvesting applications including photocatalysis, 7-13 photovoltaic devices, 14 and uorescent sensing. 5,15,16 BTZ offers a large scope for chemical derivatisation including replacing the sulfur atom with other chalcogens (O, Se and Te) or generating fused polycyclic systems, with such modications allowing the photophysical and optoelectronic properties of a BTZ D-A system to be controlled. 17,18 Beyond direction modication to the acceptor group, derivatisation of the donor aryl groups, most oen located in the 4and 7-positions (4,7-diarylBTZ), has also been explored. Recently, we have reported on the effect that changing the aryl group has on the photophysical and photoredox properties of a 4,7-diarylBTZ D-A photocatalyst system. 19 These photocatalysts were broadly assembled through the use of Suzuki-Miyaura cross-coupling, with the variation in structure achieved by varying the combination of coupling partners. A more direct approach towards aryl group modication has been realised by Zhang and coworkers, who have reported both the palladium catalysed regioselective C-H acyloxylation and halogenation of 4-aryl and 4,7-diaryl substituted BTZs using hypervalent iodine reagents (Fig. 1). 20,21 Similarly, regioselective C-H borylation of 4,7-diarylBTZs has been reported by Ingleson and coworkers through the use of BCl 3 . 22 This approach resulted in the orthoregioselective installation of a BCl 2 group that engaged in the formation of a dative bond with the BTZ nitrogen atom. 23,24 This generated a rigid, planar structure that featured extended pconjugation and reduced the separation between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The susceptibility the B-Cl bond to reaction with water allowed for the formation of a boronic acid group, which Ingleson and coworkers took advantage of to synthesise thermally activated delayed uorophores through Suzuki-Miyaura cross coupling reactions. 25 Inspired by this approach, we herein report on the regioselective ortho-phenylation of 4,7-diphenylbenzo[c] [1,2,5]thiadiazole (pH-BTZ) and 4,7-di(thiophen-2-yl)benzo[c] [1,2,5]thiadiazole (Th-BTZ) through a similar one-pot, three step strategy. The regioselective installation of a phenyl group in the ortho-position introduced steric bulk that twisted the molecule around the electron donor-acceptor torsion angle, leading to hypsochromic shis in the wavelengths of maximum absorption (l abs ) and emission (l em ), as well as changes in the lifetime of uorescence (s f ) and photoluminescence quantum yields (PLQY).

Fluorophore synthesis
Our previous studies conducted into BTZ compounds as uorophores focused on the changes in light absorption and emission that could be made by derivatisation of pH-BTZ, which exhibited a l abs at 380 nm and a l em at 482 nm in chloroform. 19 The most signicant changes were observed upon substitution of the phenyl rings with heterocycles, leading to signicant hypsochromic (e.g. 4-pyridyl groups) or bathochromic shis (e.g. 2-thienyl, 2-pyrrolyl, 2-thiazoyl groups) for both absorption and emission. In particular, substitution of the phenyl groups with Th-BTZ resulted in the l abs and l em bathochromically shiing to 446 and 552 nm respectively, driven mainly by an increase in the energy of the HOMO. We were therefore interested in applying this borylation/Suzuki-Miyaura crosscoupling approach developed by Ingleson and co-workers to both pH-BTZ and Th-BTZ as representative examples of nonplanar and planar D-A uorophores respectively.
The addition of BCl 3 (1 M in DCM) to a solution of pH-BTZ or Th-BTZ in DCM resulted in the formation of a dative bond with the BTZ nitrogen atom and borylation of the aryl C-H bond ortho-to the BTZ group (Scheme 1). 24 Aer allowing these solutions to stir overnight at room temperature, all of the volatiles were removed under reduced pressure to yield pure borylated products pH-BTZ-BCl 2 and Th-BTZ-BCl 2 in 95 and 90% yield respectively. UV-vis absorption spectra recorded for pH-BTZ-BCl 2 and Th-BTZ-BCl 2 in chloroform revealed large bathochromic shis in absorption, with maxima located at 510 and 604 nm respectively, which can be rationalised by the formation of a rigid, planar structure with extensive p-conjugation ( Fig. S10 and S14 †).
Following the successful isolation of pH-BTZ-BCl 2 and Th-BTZ-BCl 2 , the one-pot, three-step phenylation strategy described in Scheme 2 was investigated. Aer the initial borylation step, pH-BTZ-BCl 2 and Th-BTZ-BCl 2 were dissolved in a THF/water mixture to elicit formation of the boronic acid which was not isolated. Following degassing these mixture with nitrogen gas, bromobenzene (2 equivalents), Pd(PPh 3 ) 4 (5 mol%) and potassium carbonate (10 equivalents) were added and the mixture heated to 70°C. Following completion of the reaction, pH-BTZ-oPh and Th-BTZ-oPh were isolated in 55 and 57% yields, respectively.
Following the installation of the rst ortho-phenyl group to Th-BTZ, the borylation/Suzuki-Miyaura cross coupling strategy was applied a second time to form Th-BTZ-oPh 2 (Scheme 2B). This strategy was not extended to pH-BTZ-oPh as we have previously reported the synthesis of the symmetric molecule pH-BTZ-oPh 2 directly via a single Suzuki-Miyaura cross- coupling reaction from 4,7-dibromoBTZ. 19 However, pH-BTZ-oPh 2 was also characterised in parallel with the uorophores discussed in this report as an analogue of Th-BTZ-oPh 2 .

Fluorophore UV/vis absorption and emission properties
UV-vis absorption spectra were recorded for each of the uorophores in chloroform solution. From an initial value of 380 nm, the absorption of pH-BTZ underwent modest hypsochromic shis upon installing the ortho-phenyl groups (Table  1 and Fig. 2). This resulted in l abs of 377 and 373 nm for pH-BTZ-oPh and pH-BTZ respectively. Larger hypsochromic shis in absorption were observed upon ortho-phenylation of Th-BTZ and Th-BTZ-oPh. From an initial value of 446 nm, the introduction of a single ortho-phenyl group resulted in a hypsochromic shi in l abs to 432 nm, with the addition of a second to form Th-BTZ-oPh 2 further shiing the l abs to 423 nm. In both cases, the hypsochromic shi can be attributed to the sterically bulky ortho-phenyl groups increasing the donor-acceptor torsion angle, disrupting p-conjugation. This is consistent with previous observations made by Pathak et al., with regards the effect that introducing methyl groups had on the absorption proles of 4,7-diarylBTZs. 26 The hypsochromic shis we observed were more pronounced for uorophores bearing thiophene rings, as pH-BTZ was already non-planar in solution while Th-BTZ instead preferentially adopted a planar geometry and would therefore experience comparatively greater twisting.
Fluorescence lifetimes (s f ) for each of the uorophores involved in this study were measured using time-resolved photoluminescence spectroscopy (Table 1 and Fig. S17 †). For the uorophores based on pH-BTZ, successive ortho-phenylation led to an increase in s f from an initial value of 10.01 ns for pH-BTZ to 12.69 and 15.33 ns for pH-BTZ-oPh and pH-BTZ-oPh 2 respectively. This is presumably due to the steric hinderance caused by introducing the ortho-phenyl substituents, preventing rotation around the donor-acceptor dihedral bond. This would eliminate a pathway for non-radiative relaxation of the excited state which could otherwise compete with radiative relaxation. 27 This trend was also present in the measured photoluminescence quantum yields (PLQYs), which rose from 0.864 for pH-BTZ to 1.00 for both pH-BTZ-oPh and pH-BTZ-oPh 2 . This effect has previously been demonstrated in BTZ uorophores by El-Zohry et al., where intermolecular hydrogen bonding between carboxylic acid substituent groups suppressed intramolecular rotation about the electron donor-acceptor dihedral angle, ultimately enhancing PLQY. 28 The trends observed for the pH-BTZ series of uorophores were not present in the series of uorophores based on Th-BTZ, with neither s f nor the PLQYs correlating with the number of  (Fig. S17). f k r and k nr were estimated from the PLQY and s f 29 . phenyl substituents introduced to the electron donor 2-thienyl groups. s f , in particular, was largely unaffected by introducing the phenyl substituents with values measured to be in the range of 12.84-13.13 ns. This would suggest that regioselective phenylation did not impact rotation of the thiophene group relative to the BTZ group to the same degree as the phenyl groups of pH-BTZ.
To gain further insight into the effect of the ortho-phenylation on pH-BTZ and Th-BTZ, the rate constants for radiative (k r ) and non-radiative (k nr ) were estimated from the PLQY and s f using eqn (1) and (2). 29 For radiative relaxation, the overall effect of ortho-phenylation of pH-BTZ was a modest reduction in k r from 8.63 × 10 7 s −1 to 7.88 × 10 7 s −1 and 6.52 × 10 7 s −1 for pH-BTZ-oPh and pH-BTZ-oPh 2 respectively. The value of k nr was essentially reduced to zero for both pH-BTZ-oPh and pH-BTZ-oPh 2 by the increase in the PLQY to 1.00, highlighting the suppression of nonradiative relaxation pathways by ortho-phenylation. This can be directly contrasted with the effect that ortho-phenylation had on the Th-BTZ series of uorophores, where k r and k nr showed little variation in value, although k r still outweighed k nr .

Computational studies
Further characterisation was conducted through density functional theory (DFT) and time dependant-DFT (TD-DFT) analysis. Investigation of the barriers to rotation of the electron donor moiety relative to the central acceptor moiety (Fig. S21 and S22 †) shows a preferential deviation from planarity of 40°for the pH-BTZ structure which increases to a 60°deviation upon incorporation of the ortho-phenyl moiety. In contrast, Th-BTZ is shown to adopt a planar geometry with a 3 kJ mol −1 preference for the sulfur of the thiophene moiety to be orientated away from the central chalcogen. Planarity is lost upon incorporation of ortho-phenyl substituent, instead adopting a 40°deviation and inverting the orientation of the thiophene moiety, opting to place the bulkier phenyl substituent further from the central chalcogen.
Each structure containing ortho-phenyl groups showed a substantially lower rotational barrier when moving the phenyl group away from the central chalcogen, whereas rotating the phenyl group past the central chalcogen produced a larger energy barrier. In the case of pH-BTZ-oPh and pH-BTZ-oPh 2 , the energy barrier to rotation is ca. 56 kJ mol −1 , rendering this rotation unlikely (Fig. S21 †). In comparison, rotation around the BTZ-thiophene bonds in Th-BTZ-oPh and Th-BTZ-oPh 2 presents a substantially lower energy barrier of around 27 kJ mol −1 (Fig. S22 †). The reason for this lower energy barrier is most likely due to the pentagonal shape of the thiophene groups, which would slightly orientate any ortho-phenyl substituent groups they bare away from the BTZ group and reduce the steric hinderance. The lower energy barriers to internal rotation that Th-BTZ-oPh and Th-BTZ-oPh 2 present could also explain why s f and PLQY are not massively changed relative to Th-BTZ, as internal rotation is not suppressed to the same degree as pH-BTZ based uorophores.
Additionally, TD-DFT spectra were obtained for each spectra ( Fig. S19 and S20 †) which show promising alignment with those observed from experimental data (Table S2 †). Natural transition orbital (NTO) analysis of the excited state providing the major contribution to the 375 nm and 425 nm peaks of pH-BTZ and Th-BTZ, respectively, showed similar character across all structures, irrespective of ortho-functionalisation (Tables S5-S10 †). This transition, shown in Fig. 3 for the Th-BTZ structure shows a p-p* transition involving the movement of charge from the outer, electron donor groups, onto the central BTZ electron acceptor group.

Single crystal X-ray structures
Single crystals of pH-BTZ-oPh, Th-BTZ-oPh and Th-BTZ-oPh 2 suitable for X-ray diffraction were grown by slow evaporation from chloroform or acetone solution (Fig. S1-S8 †). The structural twisting was best exemplied by the crystal structure of Th-BTZ-oPh in which the thiophene ring bearing a phenyl group was twisted to an angle of 50°, while the unmodied thiophene ring remained coplanar with the BTZ group (Fig. 4). This can be contrasted with the reported crystal structure of Th-BTZ previously reported by McCulloch and coworkers, in which both thiophene rings are coplanar with the BTZ group. benzo[c] [1,2,5]thiadiazole (Th-BTZ) were all synthesised according to literature procedures (see ESI † for details). 19 All commercially available reagents were used as received and purchased from Sigma-Aldrich, Fluorochem, Apollo Scientic or Fischer Scientic. DCM was dried over 4 Å activated molecular sieves before using in borylation reactions.
NMR spectra of synthetic products were recorded using a Bruker AVIII 300 MHz spectrometer using the residual solvent peak as an internal reference. All IR spectra were recorded on solid powder/crystals using a Nicolet™ iS™ 5 FTIR spectrometer. UV-vis absorption spectra for the synthesised uorophores were obtained using a PerkinElmer Lambda 35 spectrometer in chloroform solution in quartz cuvettes with a path length of 1 cm. Emission spectra in the visible region were recorded using a PerkinElmer LS 55 uorescence spectrometer in chloroform solution using quartz cuvettes with a path length of 1 cm. The excitation wavelength used was the wavelength of maximum absorption for each individual uorophore. Single crystal X-ray structures were collected using a Bruker D8 venture using a Cu-Ka (l = 1.5418 Å) ImS 3.0 microfocus source, using the APEX3 program suite, with the crystal kept at 100.0 K during data collection. The structures were solved using Olex2, using the SHELXT structure solution program using intrinsic phasing and rened with the SHELXL renement package using least squares minimisation. [33][34][35] Synthesis of ortho-functionalised BTZ uorophores [1,2,5]thiadiazole (pH-BTZ-oPh). pH-BTZ (72 mg, 0.25 mmol) was dissolved in dry DCM (5 mL) and BCl 3 (1 M in DCM, 1.5 mmol, 1.5 mL) added. The solution was stirred at room temperature overnight under a constant stream of nitrogen. The solvent and any excess BCl 3 were removed under reduced pressure to yield a dark red powder. The residue was dissolved in THF (15 mL) and deionised water (5 mL) then the solution was stirred for 3 hours. K 2 CO 3 (346 mg, 2.5 mmol) and bromobenzene (79 mg, 0.5 mmol) were added to the reaction mixture which was then bubbled with nitrogen for 30 minutes. Pd(PPh 3 ) 4 (14 mg, 0.013 mmol) was added and then the solution was heated to 70°C for 16 hours. Following this time, the solution was cooled to room temperature then poured onto water (50 mL) and extracted with DCM (3 × 25 mL). The combined organic phases were dried over MgSO 4 and the solvent removed under reduced pressure. The crude product was recrystallised from hot methylated spirits to yield small yellow crystals that were washed with nhexane (50 mg, 55%). 1  . Th-BTZ (300 mg, 1.0 mmol) was dissolved in dry DCM (5 mL) and BCl 3 (1 M in DCM, 6 mmol, 6 mL) was added. The solution was stirred at room temperature overnight under a dynamic stream of nitrogen then the solvent and excess BCl 3 removed under reduced pressure to yield a dark blue powder. The residue was dissolved in THF (30 mL) and deionised water (10 mL) then the solution was stirred for 3 hours. K 2 CO 3 (1.3821 g, 2.5 mmol) and bromobenzene (314 mg, 2.0 mmol) were added to the reaction mixture which was then bubbled with nitrogen for 30 minutes. Pd(PPh 3 ) 4 (57 mg, 0.05 mmol) was added and then the solution was heated to 70°C for 16 hours. Following this time, the solution was cooled to room temperature then poured onto water (50 mL) and extracted with DCM (3 × 25 mL). The combined organic phases were dried over MgSO 4 and the solvent removed under reduced pressure. The crude product was then puried via silica gel columnchromatography using DCM : hexane 1 : 4 as the eluent to yield red crystals (217 mg, 57%). 1 [1,2,5]thiadiazole (Th-BTZ-oPh 2 ). Th-BTZ-oPh (188 mg, 0.5 mmol) was dissolved in dry DCM (5 mL) and BCl 3 (1 M in DCM, 3 mmol, 3 mL) was added. The solution was stirred at room temperature overnight under a dynamic stream of nitrogen then the solvent and excess BCl 3 were removed under reduced pressure to yield a dark blue powder. The residue was dissolved in THF (30 mL) and deionised water (10 mL) then the solution was stirred for 3 hours. K 2 CO 3 (691 mg, 5.0 mmol) and bromobenzene (157 mg, 1.0 mmol) were added to the reaction mixture which was then bubbled with nitrogen for 30 minutes. Pd(PPh 3 ) 4 (29 mg, 0.025 mmol) was added and then the solution was heated to 70°C for 16 hours. Following this time, the solution was cooled to room temperature then poured onto water (50 mL) and extracted with DCM (3 × 25 mL). The combined organic phases were dried over MgSO 4 and the solvent removed under reduced pressure. The crude product was then puried via silica gel columnchromatography using DCM : hexane 1 : 4 as the eluent to yield orange-red crystals (45 mg, 20%). 1

PLQY and uorescence lifetime measurements
PLQYs measurements were obtained following the conventions and considerations from Jones et al., 36 using a FLS920 spec-trouorometer (Edinburgh Instruments Ltd) equipped with an extended red-sensitive photon multiplier detector (R2658P, Hamamatsu) and an integrating sphere with a 102 mm inner diameter (Yobin Yvon) were used for all PLQY measurements. For the excitation, a 450 W xenon lamp (Xe2, Edinburgh Instruments Ltd) was employed. The samples consisting of 20 mM uorophores diluted in CHCl 3 , were contained in a square quartz cuvette with a path length of 1 cm and placed in the centre of the integrating sphere. Pure CHCl 3 was used as reference. The excitation wavelengths were set to the peak absorption of each sample with a bandwidth set to 5 nm. The excitation and emission regions were measured with a 0.25 nm step size. The associated measurement error is 3%.
Lifetimes measurements were performed using the FLS920 spectrouorometer, equipped with time-correlated single photon counting (TCSPC) electronics, and a pulsed light emitting diode (EPLED, from Edinburgh Instruments). The 405 nm excitation has an optical pulse approximately 1 ns long. The collection was recorded at the highest intensity emission, and the decay was t with a single exponential.

Conclusions
In conclusion, we have demonstrated that regioselective orthoborylation on the aryl groups of BTZ uorophores can be achieved using BCl 3 . Through subsequent hydroxydechlorination and Suzuki-Miyaura cross-coupling reactions, phenyl groups could be installed that interfered with rotation around the electron D-A bond. Evidence of this was observed both in the non-planar X-ray crystal structures and DFT calculation of the energy barrier for rotation about the electron D-A bond. In the case of uorophores based on pH-BTZ, ortho-phenylation resulted in increased uorescence lifetimes and PLQYs of up to 1.00. While ortho-phenylation of Th-BTZ produced larger changes in the absorption and emission spectra, the uorescence lifetimes and PLQYs were not as signicantly impacted. This facile one-pot, three-step approach presents an additional structural modication lever with which the optoelectronic and photophysical properties of BTZ electron D-A uorophores can be controlled. In future, we envisage that this approach could be extended beyond Suzuki-Miyaura cross-coupling strategies, by taking advantage of the versatile chemistry of boronic acids to generate bespoke BTZ electron D-A systems.

Conflicts of interest
There are no conicts to declare.